Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice

Abstract

Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB 1 ) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (.10-fold) but only 2-to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for D 9 -tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB 1 receptor functional tolerance. Thus, full FAAH inhibition combined with partial MAGL inhibition reduces neuropathic and inflammatory pain states with minimal cannabimimetic effects.

Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice

“…These findings are consistent with previous reports demonstrating that simultaneous inhibition of FAAH and MAGL produces more robust subjective, motor, and antinociceptive effects (Hruba et al, 2015; Long et al, 2009b; Owens et al, 2016; Anderson et al, 2014; Ghosh et al, 2015; Wilkerson et al, 2017) than those produced by selective inhibition of either enzyme alone. The observations that 2-AG levels are approximately three orders of magnitude higher than AEA levels in wild-type mouse brains (Ahn et al, 2009; Long et al, 2009a) and 2-AG possesses higher CB 1 receptor efficacy than AEA (Sugiura et al, 2002) are consistent with our findings that MAGL inhibitors produced a CB 1 receptor-mediated subjective stimulus, but PF-3845 lacked efficacy.…”

The cannabinoid system and pain

“…Systemic administration of JZL195 produces greater cannabimimetic effects than full inhibition of MAGL or FAAH alone (Long et al, 2009b), but unlike synthetic cannabinoid agonists, the effective dose for antinociception is significantly lower than that producing unwanted side-effects, indicating a potential therapeutic window (Adamson Barnes et al, 2016). Similarly, a recent study employed full FAAH inhibition with partial MAGL inhibition via co-administration of PF-3845 and JZL184 (Ghosh et al, 2015), producing a synergistic augmentation of antinociceptive potency in models of neuropathic and inflammatory pain, in the absence of cannabimimetic side effects, and with an apparent lack of tolerance and dependence following chronic dosing. In accordance with these data, a novel dual FAAH/MAGL inhibitor with markedly greater potency at FAAH than MAGL (SA-57 - Niphakis et al, 2013b), produces antinociception in mouse models of neuropathic and inflammatory pain (Wilkerson et al, 2016a).…”

The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

“…One such dual inhibitor, JZL195 produces augmented antinociceptive effects in mouse models of acute thermal, visceral (Sakin et al, 2015), inflammatory (Long et al, 2009b; Anderson et al, 2014) and neuropathic (Adamson Barnes et al, 2016) pain. Additionally, the combination of a high dose of the FAAH inhibitor PF3845 and a low dose of the MAGL inhibitor JZL184 produces augmented antinociceptive effects in inflammatory and neuropathic pain assays (Ghosh et al, 2015). The dual FAAH/MAGL inhibitor [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester], SA-57 (Niphakis et al, 2012), which reduces opioid withdrawal signs (Ramesh et al, 2013; Gamage et al, 2015) and serves as a discriminative stimulus in the drug discrimination paradigm (Owens et al, 2016) in mice, has yet to be tested in pain models.…”